The present invention relates to the discovery of the novel use of hydroxyl ions in a wide variety of therapeutic applications. This medicinal property of hydroxyl ions has not been observed previously due to their severe toxicity and tissue irritating effects. However, when a unique hydroxyl ion-modulating compound is used as a companion with hydroxyl ions, the harmful effects are attenuated, unmasking their previously unknown novel therapeutic activity. Thus, the invention also relates to the novel compounds that modulate and attenuate the toxic and harmful effects of hydroxyl ions. The invention includes compositions composed of hydroxyl ions and their companion modulating compounds, therapeutic methods of using such compositions and methods of preparing such compositions and their novel components.
Compositions that are applied to human or animal tissue or administered in a variety of other ways to achieve a desired therapeutic effect possess substantially neutral pH values. This is because the irritating and toxic effects of such compositions are directly related to their degree of acidity or alkalinity.
Farrish U.S. Pat. Nos. 4,767,786 and 4,868,213 disclose the use of alkali metal salts of hydroxy alkyl amine-substituted carboxylic acids to disinfect and clean animate objects, surfaces and animal tissue, and to reduce pain and itching. These patents disclose a commercially available product sold by W. R. Grace & Co. under the trademark Hampshire DEG. Since this material is a reaction product of a mixture of sodium cyanide, soda lye, formaldehyde and water, the presence of some of these agents, as well as a variety of major and minor reaction products, is expected. According to the Material Safety Data Sheet published by W. R. Grace & Co., Hampshire DEG contains, among other things, 48-49% by weight of sodium diethanolglycinate (sodium salt of N,N-bis(2-hydroxyethyl)glycine or sodium N,N-bis-(2-hydroxyethyl)aminoacetate), 1-2% by weight of sodium hydroxide and trisodium nitrilotriacetate in an amount of less than 0.5% by weight. Hampshire DEG is also known to contain minor amounts of one or more free amines and has a pH of 13-14.
As noted above, the Material Data Sheet states that Hampshire DEG includes trisodium nitrilotriacetate, which "may reasonably be anticipated to be a carcinogen" according to the Fourth Annual Report on carcinogens (NTP85-022, 1985) page 140. The trisodium nitrilotriacetate is apparently formed during the production of the sodium diethanolglycinate and is not removed during the volatilization process designed to remove amines, as disclosed in the Farrish patents. Other than Hampshire DEG, the Farrish patents do not disclose the combination of hydroxyl ions and alkali metal salts of hydroxy alkyl amine-substituted carboxylic acids, and do not suggest any direct cooperation between hydroxyl ions and such salts or that hydroxyl ions per se have any therapeutic benefits. The Farrish patents disclose that anionic surface active agents are used to reduce irritating effects from high pH, and that the carboxylic acid salts reduce the harmful effects of the anionic surface active agents.
Murtaugh U.S. Pat. No. 3,965,048 discloses drain cleaning compositions including an aqueous solution of a potassium salt of nitrilotriacetic acid, N-2-hydroxyethylimino diacetic acid, an alkylene polyamine polycarboxylic acid, or mixtures thereof and potassium hydroxide, with the composition being free of other alkali metal ions. This patent exemplifies compositions which have large molar excesses of potassium hydroxide. Also, this patent does not disclose any therapeutic or similar applications for such compositions.
Japanese Patent Application 56-45997 discloses an alkaline detergent for hard surfaces containing water, 17-25% by weight of sodium hydroxide and 4-18% by weight of sodium 2-hydroxyethyl imino-diacetate. Thus, these compositions involve large molar excesses of sodium hydroxide. No therapeutic or similar applications of such composition are disclosed.
Kita et al U.S. Pat. No. 4,915,864 discloses an aqueous solution of a strong alkali, a nonionic surface active agent and, as a solubilizing agent, one or more carboxylic acids having the formula: EQU R.sub.1 COOM.sub.1 or R.sub.2 --X--(CH.sub.2).sub.ml COOM.sub.2
in which R.sub.1 and R.sub.2 each represents a C.sub.4-18 linear aliphatic hydrocarbon group, C.sub.4-18 aromatic hydrocarbon group, M.sub.1 represents a H, an alkali metal, an aliphatic amine having a C.sub.1-4 carbon atom content, ammonia, or an alkanolamine, X represents a group selected from &gt;NH, &gt;N(CH.sub.2).sub.nl COOM.sub.2, or CHCOOM.sub.2, M.sub.2 represents a H, an alkali metal, an aliphatic amine having a C.sub.1-4 carbon atom content, ammonia, or an alkanolamine, and ml and nl independently indicate integers of 1-3. Kita et al uses large molar excesses of strong alkali and does not disclose any therapeutic or similar applications for such compositions.
Berke et al U.S. Pat. No. 4,337,269 discloses a product formed by the reaction of glycine, an alkyl substituted glycinate, or salts of these compounds with formaldehyde as a biocidal agent which inhibits microorganism growth. This patent discloses that the composition is prepared by mixing equal molar amounts of glycine and alkali metal hydroxide with formaldehyde. No excess hydroxyl ions are included, and no pharmaceutical compositions or therapeutic applications are disclosed.
Giraud-Clenet et al, C.R. Acad. Sc. Paris, Series C 1969, 268(1), p. 117-120, discloses the preparation of certain N-(beta-hydroxyethyl)-alpha-amino acid intermediates by selective hydroxyethylation. The preparation involves producing 3-(R-substituted)-4-(2-hydroxyethyl)-2-morpholones which are treated with potassium hydroxide to give alpha- N,N-bis(2-hydroxyethyl)-amino acids that are converted to amides. Only two such acids are disclosed and are used only as chemical intermediates. Further, no combinations of such acids and excess hydroxyl ions are disclosed or suggested. In addition, the methodology used by Geraud-Clenet et al to produce the acids disclosed has only limited applicability and is not effectively useable to produce many acids.